The present invention relates to systems for manipulating liquid on a substrate, and especially to systems for analysis or reaction wherein multiple liquids are transported.
As an analyzer for detecting the amount of ingredient contained in a sample, a spectral analyzer is widely used, wherein a white light from a halogen lamp or the like is irradiated at a reaction liquid, which is a mixed solution of a sample and a reagent, and then a light having transmitted through the reaction liquid is dispersed by means of a diffraction grating to extract a necessary wavelength component and determine its absorbancy, thereby measuring the amount of a desired ingredient. Alternatively, a white light may be irradiated at a reaction liquid after been dispersed with a diffraction grating. In these analyzers, conventionally, a sample and a reagent are dispensed into a reaction container made of plastic or glass, and are mixed to provide for a reaction liquid, at which light is irradiated to measure the amount of ingredient.
However, recently, for the purpose of reduction in the reagent cost and in the environmental load, there is a need for minimalizing the amount of reaction liquids used for analysis, and with the conventional scheme for minimalizing the amount of reaction liquids, the handling of liquid becomes difficult, and the scheme also has a problem that accurate measurements can not be made due to air bubbles generated during the dispensing and mixing. For this reason, there is a need for techniques to manipulate a minimal amount of liquid accurately.
As one method for manipulating a minimal amount of liquid, there is a method for transporting liquid on electrodes formed in a flat substrate, under an electrical control. In this one typical method, a liquid to be transported is converted into granular liquids, which are then sandwiched in between two opposing substrates, in which a plurality of electrodes are formed, and then a voltage is applied to the electrodes arranged along the surfaces of between the two opposing substrates thereby to transport the liquid (for example, Pollack et al., “Electrowetting-based actuation of liquid droplets for microfluidic applications”, Applied Physics Letters, Vol. 77, No. 11, Pp. 1725-1726, 2000, and Fowler et al., “ENHANCEMENT OF MIXING BY DROPLET-BASED MICROFLUIDICS”, IEEE 15th Int. Conf. MEMS January 2002, P. 97-100). A device consisting of two opposing substrates will be referred to as a “device for transporting liquid”. In this method, typically, along a liquid-transporting passage to transport liquids, multiple electrodes are formed on one of the two substrates, and one electrode coupled to the ground is provided on another substrate. If a voltage is applied to one of the electrodes underneath a granular liquid, due to the electrowetting phenomenon (for example, Vallet et al., “Electrowetting of water and aqueous solutions on poly(ethylene terephthalate) insulating films”, Polymer 37 (1996) 2465-2470) the wettability on the electrode to which the voltage is applied becomes excellent so that the granular liquid moves as to rest upon the electrode to which the voltage is applied. By repeating this, the liquid is transported.
Moreover, it is reported that liquid is distributed into branches using an array of plurality of branched electrodes, or that liquids are merged in a position where a plurality of conduits meet (for example, JP-A-10-267801). Moreover, it is also reported that one granular liquid is divided (for example, U.S. Pat. No. 6,565,727). Moreover, a system is also reported wherein a sample is transported and the measurement is carried out inside a device for transporting liquid (Srinivasan et al., “CLINICAL DIAGNOSTICS ON HUMAN WHOLE BLOOD, PLASMA, SERUM, URINE, SALIVA, SWEAT, AND TEARS ON A DIGITAL MICROFLUIDIC PLATFORM”, Micro Total Analysis Systems 2003 p. 1287-1290).
The advantages of these devices for liquid used for transporting which transport liquid include: that these are unsusceptible to air bubbles, due to the use of a substrate, as compared with the cases of using a container whose periphery is enclosed by walls; and the like. Here, there are reported two types of medium for filling the inside of the device for transporting liquid. One of them is a case where the inside is filled with oil as described in Pollack et al., Applied Physics Letters, Vol. 77, No. 11, Pp. 1725-1726, 2000, another is a case where the inside is filled with air as described in Fowler et al., IEEE 15th Int. Conf. MEMS January 2002, P. 97-100.
On the other hand, as for the method for transporting liquid in an automatic analyzer, it is reported that a segment of water solution is introduced into a conduit to transport, the conduit in which liquid such as a silicone oil being stored (for example, U.S. Pat. No. 3,479,141). Moreover, concerning apparatuses for sucking, dispensing separated liquids, or transporting them in a liquid flow, it is reported that a plurality of sample segments are transported while leaving a mutual space therebetween by means of a segment of air and a segment of immiscible liquid (for example, U.S. Pat. No. 4,259,291). Moreover, it is also reported that a liquid is enclosed by an oil droplet and is transported by the electrowetting phenomenon (Srinivasan et al., “PROTEIN STAMPING FOR MALDI MASS SPECTROMETRY USING AN ELECTROWETTING-BASED MICROFLUIDIC PLATFORM”, Lab-On-a-Chip: Platforms, Devices, and Applications, Conf. 5591, SPIE Optics East, Philadelphia, Oct. 25-28, 2004).
In the case where the inside of the device for transporting liquid is filled with oil, because a granular liquid to be transported is enclosed by oil, there are advantages in that: dirt will not likely adsorb to the surface of the device for transporting liquid: the friction between the liquid and the device for transporting liquid is reduced due to the oil; and the voltage required for moving can be reduced: evaporation of the liquid is prevented: and the like. However, because the bottom face and side face of the device for transporting liquid need to be sealed such that the oil will not leak therethrough, it takes time and efforts to mount. Moreover, a problem can be conceived in that when manipulating liquid, a flow occurs in oil, thereby giving affect to other liquids. For example, problems can be conceived in: that when introducing liquid into the device for transporting liquid, a probe for dispensing liquid, and the introduced granular liquids generate a flow in the oil, thereby moving another liquid arranged in the device for transporting liquid: and the like. In the case where liquid moves out of control, it is very likely that the liquid come in contact with other liquids to mix, or that the liquid moves away from a liquid-transporting passage, and thus the transporting may not be possible. Especially, in systems for analyzing, with respect to multiple samples and reagents, a plurality of manipulations such as dispensing, transporting, mixing, detecting, and draining need to be carried out to a plurality of liquids. For this reason, it is essential that the manipulations with respect to a certain liquid does not give effect to other liquids.
Moreover, considering an application to a system for analyzing wherein the measurement is carried out in the device for transporting liquid, a problem can be conceived in that if air bubbles come into oil from a liquid introducing port, the air bubbles will prevent the measurement in the measurement section, and so on. On the other hand, in the case where the inside of the device for transporting liquid is filled with air, there are advantages in that because the bottom face and side face of the device for transporting liquid do not need to be sealed, the mounting will be easy, and that because the periphery of liquid is filled with air, the manipulation to a certain liquid will not give effect to other liquids and an independent and stable manipulation can be carried out to a plurality of liquids. However, unlike the case where the liquid is enclosed by oil, the liquid is in contact directly with the surface of the device for transporting liquid, therefore, problems can be conceived in that the ingredient inside the liquid will likely adsorb; that the voltage required for moving is high because the friction between the liquid and the device for transporting liquid is high; that the evaporation of the liquid cannot be prevented; and the like. In the system for analyzing which uses the device for transporting liquid, in order to measure the concentration of an ingredient inside a sample, the sample being the liquid to be transported, it is essential to prevent the adsorption and evaporation of the ingredient inside the liquid.
In a scheme, wherein a liquid to be transported is enclosed by a droplet of liquid used for transporting, which will not mix with the liquid to be transported, and the liquid used for transporting is transported together with the liquid to be transported, the enclosing with the liquid used for transporting needs to be carried out adequately. Moreover, in an ordinary system for analyzing it is necessary to measure multiple samples sequentially, therefore, at the time of measuring multiple samples in this transporting scheme, the enclosing concerned needs to be carried out adequately and simply in order to prevent the contamination of the sample and improve the throughput of the measurement.